Packaging of chromatin is modified by the cell in a myriad of different ways, most profoundly through either a complete loss of histones from DNA or the establishment of (in simplistic terms) a different degree of chromatin condensation through the complex, combinatorial code of histone post-translational modifications (PTMs). These modifications are designated either to tighten or loosen chromatin in order to modulate access to the DNA sequence. This modulation influences major biological processes within the cells such as gene transcription, faithful genome duplication in dividing cells and DNA repair (Lunyak and Rosenfeld (2008) Hum Mol. Genet., 17: R28-36; Jenuwein and Allis (2001) Science 293: 1074-1080). The recent identification of enzyme systems carrying out histone modifications, together with the discovery of binding proteins that “read” PTMs on histones, has led to the proposal that the pattern of modifications acts as an information code that influences gene transcription, DNA repair, genome integrity and nuclear architecture. Evidence suggests that once a code is generated, it can serve as an independent signal that allows the recruitment of a downstream regulatory protein(s) (Lunyak and Rosenfeld (2008) Hum Mol. Genet., 17: R28-36; Jenuwein and Allis (2001) Science 293: 1074-1080; Rosenfeld et al. (2006) Genes Dev., 20: 1405-1428).
Current research links cellular and tissue aging to changes in chromatin structure in a variety of model systems. It has been shown that normal aging is accompanied by a profound loss of histone proteins from the genome (Feser et al. (2010) Mol Cell 39: 724-735). Excitingly, lifespan can be extended by manipulations that reverse these age-dependent changes in chromatin structure, indicating a pivotal role for chromatin dynamics in aging (Feser et al. (2010) Mol. Cell. 39: 724-735; McCormick and Kennedy (2010) Mol. Cell. 39: 659-661). Examples include, but are not limited to, the findings that a complete or partial knockdown of enzymes responsible for histone H3 lysine (meK9 and meK4) demethylation/methylation results in life extension (Katz et al. (2009) Cell 137: 308-320; Greer et al. (2010) Nature 466: 383-387), and that phosphorylation at serine 139 (phS139), known as γH2AX (Tanaka et al. (2006) Cell Prolif., 39: 313-323), is a critical component of DNA damage response (DDR) and cellular senescence (Sedelnikova et al. (2004) Nat. Cell Biol., 6: 168-170).
Aging cells, confronted with DNA-damage resulting from a variety of stimuli under normal, physiological conditions, make fundamental decisions either to repair DNA or trigger an apoptotic or senescence response (Vijg and Campisi (2008) Nature 454: 1065-1071; Xiao et al. (2009) Nature 457: 57-62; Cook et al. (2009) Nature 458, 591-596). Post translational modifications (PTMs) of H2AX serve as a component of the adjudication between these outcomes. In the DNA repair pathways, some chromatin modifications seem to play a critical role in marking lesions or recruiting factors involved in repair, thus facilitating the function of repair proteins. The best characterized in this context are histone H2AX and H1 phosphorylation events (van Attikum and Gasser (2005) Nat. Rev. Mol. Cell. Biol. 6: 757-765; Ju et al. (2006) Science 312: 1798-1802). It is believed however, that the full spectrum of histone PTMs relevant to aging of adult stem and somatic cells and their combinatorial patterns specific for the molecular pathways that limit longevity are unknown.
The H1 histone class proteins function at several levels of chromatin organization: it binds at the entry/exit sites of the nucleosomal core DNA to seal of the DNA wrapping at the histone octamer surface (Simpson (1978) Biochemistry 17: 5524-5531) and are a prerequisite for the formation of the next level of chromatin organization in forming 30 nm fibers of supranucleosomal chromatin (Wolffe 91989) EMBO J., 8: 527-537; Thoma et al. (1979) J. Cell Biol., 83: 403-427). Evidence indicates that histone H1 class proteins influence the accessibility of the chromosomal DNA upon DNA replication, gene transcription and repair (Ju et al. (2006) Science, 312: 1798-1802; Wolffe et al. (2000) J. Struct. Biol., 129: 102-122; Syed et al. (2010) Proc. Natl. Acad. Sci. USA, 107: 9620-9625; Nielsen et al. (2001) Molecular Cell, 7: 729-739; Zhang et al. (2012) PLoS One 7: e38829). The existence of several non-allelic variants of the H1 histone may thus provide a means to modulate the contributions of the H1 histones to supranucleosomal chromatin37,38 as well as preserve genome integrity (Vujatovic et al. (2012) Nucleic Acids Res., 40: 5402-5414). Histone H1.0 has been described in several mammalian species (Panyim and Chalkley 91969) Biochem. Biophys. Res. ommun., 37: 1042-1049) and Gjerset et al. (1982) Proc. Natl. Acad. Sci. USA, 79: 2333-2337, have demonstrated that the synthesis of H1.0 in rodents is developmentally and hormonally controlled. Since H1.0 replaces main type of H1 histones upon chromatin remodeling, it is frequently referred to as a replacement histone variant (Doenecke and Alonso 91996) Int. J. Dev. Biol., 40: 395-401). H1.0 in vivo is confined to highly differentiated cells in several cell systems but its changing pattern during development and dependence on hormonal stimuli suggests that H1.0 also plays a role upon development and differentiation (Pina and Suau (1987) FEBS Lett., 210: 161-164; Dominguez et al. (1992) Development 115: 181-185; Julien et al. (2010) Proc. Natl. Acad. Sci. USA, 107: 5483-5488). Interestingly, It has been demonstrated that progesterone receptor (PR) regulated chromatin changes are required a cooperative action of ATP-dependent remodeling, histone methylatrasferases (HMTs), and kinase activation for generic H1 displacement and is a prerequisite for the subsequent displacement of histone H2A/H2B catalyzed by PCAF and BAF (Vicent et al. (2011) Genes & Development 25: 845-862), thus suggesting that cascades of the epigenomic regulations may converge on this family of histones.